Recently, numerous reports have appeared describing the presence of liver-cell adenomas in women using oral contraceptives. Animal studies conducted at the time these agents were originally tested foretold of the possibility but it was generally ignored. Since then, carcinogenesis has come to be viewed as a multistage process composed of two general stages, initiation and promotion. Circumstantial evidence suggests that chronic ingestion of oral contraceptive agents may act as a tumor promoting agent in the liver; however, they have never been tested using a initiation-promotion protocol. The objective of the present study is to evaluate the liver tumor promoting activity of two oral contraceptive agents, norethindrone and mestranol. Male and female Sprague-Dawley rats will be initiated by treatment with a low dose of 2-acetylaminofluorene and diethylnitrosamine, respectively. Subsequently, the animals will be fed diet containing both of these agents at 3 different levels or mestranol alone. Animals will be killed after 3,6 and 12 months and various biochemical and histochemical analyses performed to detect and quantitate the presence of atypical hepatocellular areas (i.e. hyperplastic nodules, adenomas, carcinomas). Other organs will be analyzed at sacrifice and where indicated, will be prepared for histological evaluation. The results of this study should shed some new light on the "carcinogenic potential" of oral contraceptive agents in light of current theories of the mechanisms of carcinogenesis.